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The normal role of Aβ is intimately tied up with synaptic electrophysiology. On the flip side, disturbances in the regulatory interplay between synaptic activity and AβPP processing could yield clues to a better explanation of how Aβ accumulation contributes to a cascade ending with cognitive decline. This, in a nutshell, summarizes a report in tomorrow's Neuron by Flavio Kamenetz and Roberto Malinow at Cold Spring Harbor Laboratory, New York, with collaborators elsewhere. Alzforum reported on these experiments in more detail when Malinow presented them at a workshop last November in Orlando, Florida, (see ARF related news story). Kamenetz et al. recorded synaptic activity in hippocampal slices of AβPP-transgenic mice. They found that synaptic activity modulates the generation of Aβ peptides, with BACE cleavage being the key step, and that, in turn, excess Aβ depresses excitatory NMDA receptor-related synaptic transmission. Under physiological conditions, this might serve to keep a lid on neuronal hyperactivity, the authors propose, assigning Aβ a normal role in feedback control to keep the synapse in homeostasis.—Gabrielle Strobel

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This is great must read report that discusses normal physiologic role for amyloid beta and adds to the expanding failure of
Alzheimer's amyloid dogma (Br
Med J,
23 March 2003) at the highest possible level, in Neuron journal.
The only pity (but easy to understand, see Science
SAGE KE, 21 Feb 2003) thing is that it is published t h r e e
y e a r s (!) after its' presentation at the Society for Neuroscience Annual
Meeting 2000 (Vol.26, 491 see
Abstract). We had a chance to comment on this report at earlier ARF
news commentary (AlzForum,
22 Nov 2002, with regard to the J. Neurosci. article by Lazarovet al), in our SFN 2002 proceedings article (Neurobiol
Lipids, 1, 6) and extended related scientific
correspondence.

The normal role of AβPP and Aβ in the brain has been one of the most puzzling problems for the Alzheimer’s field, and even after years of effort, this problem remains unsolved. In today’s Neuron, Kamenetz et al. provide evidence for the role of Aβ in regulating neuronal excitability, which may shed light both on Aβ’s normal role in neuronal function and its role in AD pathogenesis.

Roberto Malinow’s group have been pioneers in the field of synaptic transmission and plasticity, and have used their elegant electrophysiological techniques to address the effects of acute AβPP expression on synaptic physiology. Through the use of organotypic hippocampal slice cultures and the sindbis virus expression method, the authors were able to endogenously overexpress AβPP, mutant AβPP and various AβPP derivatives. The authors were also able to evaluate the effects of neuronal activity on Aβ levels; they found that Aβ levels rose with increasing activity and fell with decreasing activity, and, furthermore, that this regulation occurred at the level of BACE cleavage. Overexpression of AβPP led to acute depression of synaptic transmission both in AMPA- and NMDA-mediated synaptic currents. This effect was blocked by γ-secretase inhibition and was mimicked by overexpression of the β-C-terminal fragment of AβPP (the product of BACE cleavage), thus implying that Aβ was mediating the depression in transmission. Suppression of neuronal activity blocked Aβ-mediated synaptic depression and, furthermore, required NMDA receptor activation, as NMDA blockade (which doesn’t affect overall neuronal excitability) also blocked Aβ-mediated depression.

Synaptic transmission was recorded from postsynaptic neurons that overexpressed AβPP, but could AβPP overexpression affect neighboring uninfected cells? The authors addressed this question by recording from neurons that were not themselves infected with AβPP, but were surrounded by cells that were, and then comparing the response with that of an uninfected neuron surrounded by other uninfected neurons. The results from this experiment showed that secreted Aβ could also depress transmission.

Finally, the authors showed that Aβ can act as a negative feedback regulator of neuronal activity. A pairing protocol was used to induce LTP in slices of transgenic mice overexpressing the Swedish mutation of APP. LTP was impaired as compared with wild-type mice, and this effect was blocked by a γ-secretase inhibitor. Although it would have been good to replicate this finding using acute expression of AβPP, the authors contend that the sudden increase in activity leads to an increase in Aβ and a decrease in transmission which offsets LTP. Repeated LTP-inducing stimuli in wild-type animals in the presence of a γ-secretase inhibitor did result in significantly larger potentiation, and thus the authors conclude that Aβ-induced depression can be recruited in normal animals.

The findings from this study have several implications for AD. One of the best correlates for the severity of cognitive deficits in AD is synaptic loss (Scheff et al., 1990; Terry et al., 1991). In fact, based on computer models of neuronal networks, it has been suggested that the loss of synapses can explain all the cognitive symptoms of AD, and that the initial stages of dementia can even occur from synaptic dysfunction that precedes synaptic loss (Horn et al., 1996). All the AβPP overexpressing transgenic mice so far studied exhibit impairments in synaptic functioning. LTP impairments, without deficits in basal transmission, have been observed in four- to five-month-old (Larson et al., 1999) and five- to seven-month-old mice (Moechars et al., 1999), both prior to plaque deposition and 16-month-old mice with plaques (Chapman et al., 1999). Others find impaired synaptic transmission but no change in LTP in two- to four-month-old mice, prior to plaque deposition (Hsia et al., 1999) and 12- to 18-month-old mice with plaques (Fitzjohn et al., 2001). Basal transmission and LTP deficits have also been observed in mice that develop both plaque and tau pathology, and were evident at an age prior to plaque and tangle formation (Shepherd et al., 2002). It is conceivable that impairments in plasticity processes such as LTP, which are thought to underlie at least some forms of learning and memory, could result in the initial cognitive dysfunction in AD. If so, treatments that only affect plaque deposition in the late stages of AD may not alleviate all the symptoms of the disease. Severe synaptic depression of activity via Aβ may also result in loss of synapses in a use-it-or-lose-it manner. This study also opens up the intriguing possibility that changes in neuronal activity in the aging brain, perhaps brought on by environmental or genetic triggers, may cause disruption of Aβ’s feedback system, ultimately resulting in full-blown AD.

This paper opens up a new avenue of exploration in AD and possible therapeutic targets. What is the mechanism by which Aβ affects synaptic transmission? How does synaptic activity affect BACE cleavage? Why do BACE and AβPP knockout mice show no severe neuronal phenotype? What is the role of NMDA receptors in the signaling pathway induced by Aβ? These are just some of the intriguing questions that now remain to be explored. This paper shows the benefits of utilizing techniques and knowledge gained from studies in normal synaptic functioning to investigate a neurologic disease. Hopefully this is just the start of a synthesis of basic neuroscience and disease research.